Related Experiment Video
Updated: Jul 31, 2026
Screening Assays to Characterize Novel Endothelial Regulators Involved in the Inflammatory Response
Published on: September 15, 2017
Inhibitory effects of cyclic AMP elevating agents on lipopolysaccharide (LPS)-induced microvascular permeability
1Department of Pharmacology, Tokyo Women's Medical University, School of Medicine, Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. kirie@research.twmu.ac.jp
Abstract:
Anti-inflammatory effects of cyclic AMP elevating agents were examined in a mouse model of lipopolysaccharide (LPS)-induced microvascular permeability change. Vascular permeability on the back skin was measured by the local accumulation of Pontamine sky blue (PSB) after subcutaneous injection of LPS (400 microg site-1) from Salmonella typhimurium. Dye leakage in the skin was significantly increased 2 h after injection of LPS. This LPS-induced dye leakage was suppressed by phosphodiesterase inhibitors, including pentoxifylline (160 mg kg-1), milrinone (5 - 10 mg kg-1), rolipram (0.5 - 10 mg kg-1) and zaprinast (5 - 10 mg kg-1). The dye leakage was also inhibited by beta-adrenoceptor agonists, including isoproterenol (0.5 - 5 mg kg-1) and salbutamol (0.05 - 5 mg kg-1), an adenylate cyclase activator, forskolin (5 mg kg-1), and a cell permeable cyclic AMP analogue, 8-bromo-cyclic AMP (8-Br-cAMP, 10 mg kg-1). LPS caused a transient increase in serum TNF-alpha level peaking at 1 h after the injection. This increase in serum TNF-alpha was completely blocked by a pretreatment with pentoxifylline (160 mg kg-1), milrinone (5 mg kg-1), rolipram (1 mg kg-1), zaprinast (10 mg kg-1), salbutamol (0.5 mg kg-1), forskolin (1 mg kg-1) and 8-Br-cAMP (10 mg kg-1). LPS caused an increase in serum IL-1alpha level peaking at 3 h after injection. This increase in serum IL-1alpha was not significantly suppressed by the cyclic AMP elevating agents. Our study suggests that cyclic AMP elevating agents attenuate LPS-induced microvascular permeability change by suppressing TNF-alpha up regulation.
Insights
Cyclic AMP elevating agents reduce inflammation and vascular permeability in mice exposed to lipopolysaccharide (LPS). These agents suppress tumor necrosis factor-alpha (TNF-alpha) to mitigate LPS-induced effects.
Area of Science:
- Pharmacology
- Immunology
- Physiology
Background:
- Lipopolysaccharide (LPS) from Salmonella typhimurium induces microvascular permeability changes.
- Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1alpha (IL-1alpha) are key inflammatory mediators in LPS responses.
Purpose of the Study:
- To investigate the anti-inflammatory effects of cyclic AMP (cAMP) elevating agents on LPS-induced microvascular permeability.
- To determine the impact of these agents on TNF-alpha and IL-1alpha levels in vivo.
Main Methods:
- A mouse model was used to induce microvascular permeability with LPS.
- Vascular permeability was quantified by Pontamine sky blue (PSB) dye leakage.
- Serum cytokine levels (TNF-alpha, IL-1alpha) were measured using ELISA.
- Various cAMP elevating agents, including phosphodiesterase inhibitors and beta-adrenoceptor agonists, were administered.
Main Results:
- LPS significantly increased vascular permeability and serum TNF-alpha and IL-1alpha levels.
- Cyclic AMP elevating agents, such as pentoxifylline, milrinone, rolipram, zaprinast, isoproterenol, salbutamol, forskolin, and 8-bromo-cyclic AMP, effectively suppressed LPS-induced dye leakage.
- These agents also completely blocked the transient increase in serum TNF-alpha.
- However, the increase in serum IL-1alpha was not significantly affected by the cAMP elevating agents.
Conclusions:
- Cyclic AMP elevating agents demonstrate significant anti-inflammatory properties by attenuating LPS-induced microvascular permeability.
- The mechanism involves the suppression of TNF-alpha upregulation, highlighting the role of cAMP in modulating inflammatory responses.
